Method to alleviate the symptoms of PMS

ABSTRACT

The invention relates to methods for treating symptoms of PMS and PMDD including muscle ache, bloating, cramping, acne, tender breasts, bloating, fatigue, difficulty concentrating, diminished impulse control, irritability, anxiety, tension, anger, depression, insomnia and/or rapid fluctuations in mood (mood swings). The method comprises administration of a pharmaceutical composition comprising oxaloacetate, oxaloacetate salts, oxaloacetic acid and/or anhydrous enol-oxaloacetate.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. patent applicationSer. No. 16/335,652, which adopts the international filing date of Sep.21, 2017, which is a national stage application under 35 U.S.C. § 371 ofInternational Application No. PCT/US2017/052718, filed internationallyon Sep. 21, 2017, which claims the benefit of U.S. ProvisionalApplication No. 62/398,319, filed Sep. 22, 2016, the contents of whichare hereby incorporated by reference in their entirety.

TECHNICAL FIELD

The present application relates generally to methods for treatingsymptoms of premenstrual syndrome (PMS), including PremenstrualDysphoric Disorder (PMDD), comprising administering a compositioncomprising oxaloacetate to a subject in need thereof.

BACKGROUND

Premenstrual Syndrome (PMS) is a group of physical and mental symptomswhich occur cyclically beginning about seven to fourteen days prior tomenses in the luteal phase of the menstrual cycle. Menstruation occursin women from the age of about twelve to thirteen (on average) untilapproximately 50 years old. The menstrual cycle averages abouttwenty-eight days with some variation. Common PMS symptoms includemuscle ache, bloating, cramping, acne, tender breasts, bloating,fatigue, difficulty concentrating, diminished impulse control,irritability, anxiety, tension, anger, depression, feeling “out ofcontrol”, insomnia and rapid fluctuations in mood (mood swings) Suicidalthoughts are also sometimes reported. The symptoms typically resolvewith the start of menstruation. While there are commercially availabletreatments for physical discomforts, acne, and bloating, there are feweroptions available for fatigue, difficulty concentrating, diminishedimpulse control, irritability, anxiety, tension, anger, depression,feeling “out of control”, suicidal thoughts, insomnia and rapidfluctuations in mood (mood swings).

Premenstrual Dysphoric Disorder (PMDD) is a severe form of PMS thataffects 3-8% of menstruating women. Additional information on both PMSand PMDD can be found in the Diagnostic and Statistical Manual of MentalDisorders, Fifth Edition, edited by the American PsychiatricAssociation. Treatment of the many of the symptoms of PMDD is largelywith antidepressants that modulate serotonin levels in the brain viaserotonin reuptake inhibitors (SRIs). These lead to an increase inextracellular concentrations of serotonin. These SRIs can havedevastating side effects, including sexual dysfunction and suicidalbehavior. Additional SRI side effects can include insomnia, skin rashes,headaches, joint and muscle pain, stomach upset, nausea, and diarrhea,thereby making some of the PMDD symptoms worse.

There have been some treatments for PMS and PMDD: U.S. Pat. No.8,680,084 provides for a method of treating PMS and PMDD with oralcontraceptives. U.S. Pat. Nos. 8,338,396 and 7,858,605 also provide forthis method.

U.S. Pat. No. 8,399,432 uses a pharmaceutical/nutritional compositionfor PMS and PMDD using phospholipase-D.

U.S. Pat. No. 8,124,598 discloses the use of 7-keto DHEA for treatingPMS.

U.S. Pat. No. 7,897,147 uses botulinum toxin to treat symptoms ofpremenstrual disorder.

U.S. Pat. No. 6,987,101 uses gestagen (drospirenone) for treating PMDD.

U.S. Pat. Nos. 6,322,823/6,174,542, 5,612,061, 5,569,459, 5,498,631,5,654,011, 5,707,630 and 5,760,630 all contain mixtures of vitamins,minerals, essential oils and dietary supplements for the treatment ofPMS.

U.S. Pat. No. 6,057,439 provides for the use of steroids to treat PMS.

U.S. Pat. No. 7,4373,426 uses yeast extract as a method to inhibitreuptake of serotonin and norepinephrine for the treatment of PMS.

U.S. Pat. No. 8,772,301 (Hardy, et al.) provides for compounds thatmodulate the activity of metabotropic glutamate receptor 5 (mGluR5) inthe central nervous system or the periphery for the treatment of PMS andPMDD.

Gao, et al, “Shu-Yu capsule, a Traditional Chinese Medicine formulation,attenuates premenstrual syndrome depression induced by chronic stressconstraint” Molecular Medicine Reports, 10:2942-2948 (2014) showefficacy with a herbal formulation to reduce the depression of glutamatein a rat model of PMS, indicating that low glutamate levels may be theproblem in PMS.

Oxaloacetate is a small molecule human metabolite with highbioavailability involved in many reactions in the body, including thecitric cycle within the mitochondria, gluconeogenesis, urea cycle,glyoxylate cycle, amino acid synthesis, and fatty acid synthesis.

Oxaloacetate has been examined for the following conditions:

-   -   As a mimic of calorie restriction (Cash, U.S. Pat. No.        2,005,316295 Australia)    -   To Increase human lifespan (Cash, U.S. Pat. No. 5,268,362 Japan)    -   For Cancer (Cash, EPO 05 854 787.8-1464, Canada 2,589,995)    -   For Parkinson's and Alzheimer Disease (Cash, USPTO 20080279786)    -   To Activate AMPK (Cash, USPTO 20130143930)    -   For diabetes (Yoshikawa, “Studies on Anti-diabetic Effect of        Sodium Oxaloacetate” Tohoku J. exp. Med, 1968, 96, 127-141)    -   For closed head injury (Zlotnik, A et al, “The Neuroprotective        Effects of Oxaloacetate in Closed Head Injury in Rats is        Mediated by its Blood Glutamate Scavenging Activity”, J        Neurosurg Anesthesiol 21, 3 Jul. 2009    -   For protection against pesticides (Ruban, A et al, “Blood        glutamate scavenging as a novel neuroprotective treatment for        paraoxon intoxication” Journal of Cerebral Blood Flow &        Metabolism (2014) 34, 221-227)    -   For epileptic seizures Carvalho, et al, “Neuroprotective effect        of pyruvate and oxaloacetate during pilocarpine induced status        epilepticus in rats” Neurochemistry International 58 (2011        385-390 also Kriegler, S US Patent application 20060217303)    -   For protection against some poisons, such as Kainic acid        (Yamamoto, et al, “Effect of alpha-ketoglutarate and        oxaloacetate on brain mitochondrial DNA damage and seizures        induced by Kainic acid in mice” Toxicology Letters 143 (2003)        115-122

All references cited herein, including patent applications andpublications, are incorporated by reference in their entirety.

SUMMARY OF THE INVENTION

In some aspects, the present invention is directed to methods fortreating the symptoms of Premenstrual Syndrome (PMS) with a therapeuticcontaining one or more oxaloacetate compounds from the group of anoxaloacetate, an oxaloacetate salt, and/or an oxaloacetic acid(hereinafter, “oxaloacetate” in this specification). In some aspects,the present invention is directed to methods for treating the symptomsof Premenstrual Dysphoric Disorder (PMDD) with a therapeutic containingone or more oxaloacetate compounds from the group of an oxaloacetate, anoxaloacetate salt, and/or an oxaloacetic acid (hereinafter,“oxaloacetate” in this specification). These symptoms include moodswings, anger, anxiety, depression and fatigue.

In some embodiments of the invention, the oxaloacetic acid for use inmethods to treat PMS will be in a stable form such as anhydrousenol-oxaloacetic acid. In some embodiments of the invention, theoxaloacetic acid for use in methods to treat PMDD will be in a stableform such as anhydrous enol-oxaloacetic acid.

In some embodiments of the invention, the oxaloacetate compound furthercomprises an acceptable pharmaceutical carrier. This carrier can beencapsulation agents such as hypromellose capsules or other lowwater-content capsules. Alternatively, the oxaloacetate can becompressed into a tablet with such carriers as calcium carbonate,dicalcium phosphate, erythitol, vegetable steric acid, and ascorbylpalmitate. Further, said oxaloacetate, can be delivered via a two-phasesystem, in which water or other water based fluids are held separatelyfrom said oxaloacetate, and only combined just prior to ingestion. Stillfurther, said oxaloacetate can be placed in a low-water contenttransdermal patch and delivered trans-dermally. Yet still further, saidoxaloacetate can be mixed with water and a pH buffer and thenimmediately delivered through an inhalation system. Said oxaloacetatecan also be delivered to the body via suppository or when mixed withwater based fluids and a pH modifier, via injection or intravenousinfusion.

In another embodiment of the invention, said oxaloacetate can becombined with a pain reliever and/or an anti-bloating agent for thesymptoms of cramping and bloating associated with PMS, respectively. Inanother embodiment of the invention, said oxaloacetate can be combinedwith a pain reliever and/or an anti-bloating agent for the symptoms ofcramping and bloating associated with PMDD, respectively.

In some embodiments, the oxaloacctatc compound comprises a water barrierto shield the compound from absorbing atmospheric moisture to assureproper shelf life and prevent degradation into carbon dioxide andpyruvate.

In some aspects, the invention provides a method for treating one ormore symptoms of premenstrual syndrome (PMS) in an individual, themethod comprising administering an effective amount of a compositioncomprising an oxaloacetate, an oxaloacetic acid, or an oxaloacetate saltto an individual in need thereof; wherein the one or more symptoms ofPMS include one or more of acne, tender breasts, bloating, fatigue,difficulty concentrating, diminished impulse control, irritability,anxiety, tension, anger, depression, suicidal thoughts, insomnia, orcramping. In some embodiments, the method is for treating two or moresymptoms of PMS in an individual, wherein the two or more symptoms ofPMS include two or more of acne, tender breasts, bloating, fatigue,difficulty concentrating, diminished impulse control, irritability,anxiety, tension, anger, depression, suicidal thoughts, insomnia, orcramping. In some embodiments, the method is for treating three or moresymptoms of PMS in an individual, wherein the three or more symptoms ofPMS include three or more of acne, tender breasts, bloating, fatigue,difficulty concentrating, diminished impulse control, irritability,anxiety, tension, anger, depression, suicidal thoughts, insomnia, orcramping. In some embodiments, the symptoms of PMS include acne,bloating, fatigue, irritability, anxiety, anger, depression, insomnia orcramping. In some embodiments, the one or more symptoms of PMS furthercomprises mood swings.

In some embodiments of the above aspects and embodiments, theoxaloacetate or oxaloacetic acid is anhydrous enol-oxaloacetate. In someembodiments, the composition further comprises a pharmaceutical deliveryagent. In some embodiments, the pharmaceutical delivery agent isselected amongst the group of capsules, coating agents, encapsulatingagents, transdermal patches, dissolving lozenges, suppositories andbiphasic delivery systems. In some embodiments, the pharmaceuticaldelivery agent prevents or reduces exposure of the oxaloacetate towater. In some embodiments, the composition further comprises a pHmodifier. In some embodiments, wherein the pH modifier is sodiumhydroxide or calcium carbonate.

In some aspects, the invention provides a method for treatingPremenstrual Dysphoric Disorder (PMDD) in an individual, the methodcomprising administering an effective amount of a composition comprisingan oxaloacetate, an oxaloacetic acid, or an oxaloacetate salt in theindividual in need thereof. In some embodiments, the invention providesa method for treating one or more symptoms of PMDD in an individual, themethod comprising administering an effective amount of a compositioncomprising an oxaloacetate, an oxaloacetic acid, or an oxaloacetate saltto an individual in need thereof; wherein the one or more symptoms ofPMS include one or more of acne, tender breasts, bloating, fatigue,difficulty concentrating, diminished impulse control, irritability,anxiety, tension, anger, depression, suicidal thoughts, insomnia, orcramping. In some embodiments, the method is for treating two or moresymptoms of PMS in an individual, wherein the two or more symptoms ofPMS include two or more of acne, tender breasts, bloating, fatigue,difficulty concentrating, diminished impulse control, irritability,anxiety, tension, anger, depression, suicidal thoughts, insomnia, orcramping. In some embodiments, the method is for treating three or moresymptoms of PMS in an individual, wherein the three or more symptoms ofPMS include three or more of acne, tender breasts, bloating, fatigue,difficulty concentrating, diminished impulse control, irritability,anxiety, tension, anger, depression, suicidal thoughts, insomnia, orcramping. In some embodiments, the symptoms of PMS include acne,bloating, fatigue, irritability, anxiety, anger, depression, insomnia orcramping. In some embodiments, the one or more symptoms of PMS furthercomprises mood swings.

In some embodiments of the above aspects and embodiments, theoxaloacetate or oxaloacetic acid is anhydrous enol-oxaloacetate. In someembodiments, the composition further comprises a pharmaceutical deliveryagent. In some embodiments, the pharmaceutical delivery agent isselected amongst the group of capsules, coating agents, encapsulatingagents, transdermal patches, dissolving lozenges, suppositories andbiphasic delivery systems. In some embodiments, the pharmaceuticaldelivery agent prevents or reduces exposure of the oxaloacetate towater. In some embodiments, the composition further comprises a pHmodifier. In some embodiments, wherein the pH modifier is sodiumhydroxide or calcium carbonate.

In some embodiments of the above aspects and embodiments, thecomposition comprises about 100 or about 200, about 300 or about 400 mgoxaloacetate (e.g., anhydrous oxaloacetate). In some embodiments, about200 mg oxaloacetate is administered to the individual per day. In someembodiments, the composition is administered over a period of about oneday, two days, three days, four days or five days. In some embodiments,the composition is administered to the individual about one day, twodays, three days, four days or five days prior to menses. In someembodiments, administration of the composition is initiated upondetection of one or more symptoms of PMS.

In some embodiments, the composition is administered in combination witha pain reliever. In some embodiments, the pain reliever isacetaminophen, ibuprofen, or naproxen. In some embodiments, about 500 mgacetaminophen is administered to the individual. In some embodiments,about 400 mg ibuprofen is administered to the individual. In someembodiments, about 220 mg naproxen sodium is administered to theindividual. In some embodiments, the composition is administered incombination with an anti-bloating agent. In some embodiments, theanti-bloating agent is pyrilamine maleate or pamabrom. In someembodiments, about 15 mg pyrilamine maleate is administered to theindividual. In some embodiments, about 25 mg pamabrom is administered tothe individual. In some embodiments, the composition is administeredwith a pain reliever and with an anti-bloating agent.

In some aspects, the invention provides a composition comprising anoxaloacetate, an oxaloacetic acid, or an oxaloacetate salt and ananti-bloating agent. In some embodiments, the anti-bloating agent ispyrilamine maleate or pamabrom. In some embodiments, the compositioncomprises about 15 mg pyrilamine maleate. In some embodiments, thecomposition comprises about 25 mg pamabrom. In some aspects, theinvention provides a composition comprising an oxaloacetate, anoxaloacetic acid, or an oxaloacetate salt and a pain reliever. In someembodiments, the pain reliever is acetaminophen, ibuprofen, or naproxen.In some embodiments, the composition comprises about 500 mgacetaminophen. In some embodiments, the composition comprises about 400mg ibuprofen. In some embodiments, the composition comprises about 220mg naproxen sodium. In some embodiments, the composition comprisesoxaloacetate, a pain reliever and an anti-bloating agent. In someembodiments, the oxaloacetate or oxaloacetic acid is anhydrousenol-oxaloacetate. In some embodiments, the composition furthercomprises a pharmaceutical delivery agent. In some embodiments, thepharmaceutical delivery agent is selected amongst the group of capsules,coating agents, encapsulating agents, transdermal patches, dissolvinglozenges, suppositories and biphasic delivery systems. In someembodiments, the pharmaceutical delivery agent prevents or reducesexposure of the oxaloacetate to water. In some embodiments, thecomposition further comprises a pH modifier. In some embodiments,wherein the pH modifier is sodium hydroxide or calcium carbonate. Insome embodiments, the composition comprises about 10 mg oxaloacetate toabout 1000 mg oxaloacetate. In some embodiments, the compositioncomprises about 100 mg or about 200 mg oxaloacetate.

In some aspects, the invention provides a method for treating one ormore symptoms of premenstrual syndrome (PMS) in an individual, themethod comprising administering an effective amount of a compositioncomprising an oxaloacetate, an oxaloacetic acid, or an oxaloacetate saltto an individual in need thereof; wherein the one or more symptoms ofPMS include one or more of anger, anxiety, depression, or irritability.In some embodiments, the method is for treating two or more symptoms ofpremenstrual syndrome (PMS) in an individual, wherein the two or moresymptoms of PMS include one or more of anger, anxiety, depression, orirritability. In some embodiments, the method is for treating three ormore symptoms of premenstrual syndrome (PMS) in an individual, whereinthe three or more symptoms of PMS include three or more of anger,anxiety, depression, or irritability. In some embodiments, the method isfor treating anger, anxiety, depression, or irritability. In someembodiments, the one or more symptoms of PMS further comprises moodswings. In some embodiments, the PMS is PMDD. In some embodiments, theoxaloacetate or oxaloacetic acid is anhydrous enol-oxaloacetate. In someembodiments, the composition further comprises a pharmaceutical deliveryagent. In some embodiments, the pharmaceutical delivery agent isselected amongst the group of capsules, coating agents, encapsulatingagents, transdermal patches, dissolving lozenges, suppositories andbiphasic delivery systems. In some embodiments, the pharmaceuticaldelivery agent prevents or reduces exposure of the oxaloacetate towater. In some embodiments, the composition further comprises a pHmodifier. In some embodiments, wherein the pH modifier is sodiumhydroxide or calcium carbonate. In some embodiments, the compositioncomprising the oxaloacetate is administered in combination with a painreliever. In some embodiments, the pain reliever is acetaminophen,ibuprofen, or naproxen. In some embodiments, about 500 mg acetaminophenis administered to the individual. In some embodiments, about 400 mgibuprofen is administered to the individual. In some embodiments, about220 mg naproxen sodium is administered to the individual. In someembodiments, the composition comprising the oxaloacetate is administeredin combination with an anti-bloating agent. In some embodiments, theanti-bloating agent is pyrilamine maleate or pamabrom. In someembodiments, about 15 mg pyrilamine maleate is administered to theindividual. In some embodiments, about 25 mg pamabrom is administered tothe individual. In some embodiments, the composition is administeredwith a pain reliever and with an anti-bloating agent.

In some aspects, the invention provides a method for treating one ormore symptoms of premenstrual syndrome (PMS) in an individual, themethod comprising administering an effective amount of a compositioncomprising an oxaloacetate, an oxaloacetic acid, or an oxaloacetate saltto an individual in need thereof; wherein the one or more symptoms ofPMS is fatigue or cramps. In some embodiments, the PMS is PMDD. In someembodiments, the oxaloacetate or oxaloacetic acid is anhydrousenol-oxaloacetate. In some embodiments, the composition furthercomprises a pharmaceutical delivery agent. In some embodiments, thepharmaceutical delivery agent is selected amongst the group of capsules,coating agents, encapsulating agents, transdermal patches, dissolvinglozenges, suppositories and biphasic delivery systems. In someembodiments, the pharmaceutical delivery agent prevents or reducesexposure of the oxaloacetate to water. In some embodiments, thecomposition further comprises a pH modifier. In some embodiments,wherein the pH modifier is sodium hydroxide or calcium carbonate. Insome embodiments, the composition comprising the oxaloacetate isadministered in combination with a pain reliever. In some embodiments,the pain reliever is acetaminophen, ibuprofen, or naproxen. In someembodiments, about 500 mg acetaminophen is administered to theindividual. In some embodiments, about 400 mg ibuprofen is administeredto the individual. In some embodiments, about 220 mg naproxen sodium isadministered to the individual. In some embodiments, the compositioncomprising the oxaloacetate is administered in combination with ananti-bloating agent. In some embodiments, the anti-bloating agent ispyrilamine maleate or pamabrom. In some embodiments, about 15 mgpyrilamine maleate is administered to the individual. In someembodiments, about 25 mg pamabrom is administered to the individual. Insome embodiments, the composition is administered with a pain relieverand with an anti-bloating agent.

In some aspects, the invention provides a method for treating two ormore symptoms of premenstrual syndrome (PMS) in an individual, themethod comprising administering an effective amount of a compositioncomprising an oxaloacetate, an oxaloacetic acid, or an oxaloacetate saltto an individual in need thereof; wherein the one or more symptoms ofPMS is wherein the one or more symptoms of PMS include one or more ofanger, anxiety, depression, or irritability and one or more symptoms ofPMS is fatigue or cramps. In some embodiments, the PMS is PMDD. In someembodiments, the oxaloacetate or oxaloacetic acid is anhydrousenol-oxaloacetate. In some embodiments, the composition furthercomprises a pharmaceutical delivery agent. In some embodiments, thepharmaceutical delivery agent is selected amongst the group of capsules,coating agents, encapsulating agents, transdermal patches, dissolvinglozenges, suppositories and biphasic delivery systems. In someembodiments, the pharmaceutical delivery agent prevents or reducesexposure of the oxaloacetate to water. In some embodiments, thecomposition further comprises a pH modifier. In some embodiments,wherein the pH modifier is sodium hydroxide or calcium carbonate. Insome embodiments, the composition comprising the oxaloacetate isadministered in combination with a pain reliever. In some embodiments,the pain reliever is acetaminophen, ibuprofen, or naproxen. In someembodiments, about 500 mg acetaminophen is administered to theindividual. In some embodiments, about 400 mg ibuprofen is administeredto the individual. In some embodiments, about 220 mg naproxen sodium isadministered to the individual. In some embodiments, the compositioncomprising the oxaloacetate is administered in combination with ananti-bloating agent. In some embodiments, the anti-bloating agent ispyrilamine maleate or pamabrom. In some embodiments, about 15 mgpyrilamine maleate is administered to the individual. In someembodiments, about 25 mg pamabrom is administered to the individual. Insome embodiments, the composition is administered with a pain relieverand with an anti-bloating agent.

In some embodiments of the above aspects and embodiments, thecomposition comprises about 100 or about 200, about 300 or about 400 mgoxaloacetate (e.g., anhydrous oxaloacetate). In some embodiments, about200 mg oxaloacetate is administered to the individual per day. In someembodiments, the composition is administered over a period of about oneday, two days, three days, four days or five days. In some embodiments,the composition is administered to the individual about one day, twodays, three days, four days or five days prior to menses. In someembodiments, administration of the composition is initiated upondetection of one or more symptoms of PMS. In some embodiments, thecomposition is administered in combination with a pain reliever. In someembodiments, the pain reliever is acetaminophen, ibuprofen, or naproxen.In some embodiments, about 500 mg acetaminophen is administered to theindividual. In some embodiments, about 400 mg ibuprofen is administeredto the individual. In some embodiments, about 220 mg naproxen sodium isadministered to the individual. In some embodiments, the composition isadministered in combination with an anti-bloating agent.

In some aspects, the invention provides a unit dose of oxaloacetate fortreating PMS, the unit dose comprising about 10 mg to about 1000 mgoxaloacetate and a pain reliever. In some embodiments, the pain relieveris acetaminophen, ibuprofen, or naproxen. In some embodiments, the unitdose comprises about 500 mg acetaminophen. In some embodiments, the unitdose comprises about 400 mg ibuprofen. In some embodiments, the unitdose comprises about 220 mg naproxen sodium. In some aspects, theinvention provides a unit dose of oxaloacetate for treating PMS, theunit dose comprising about 10 mg to about 1000 mg oxaloacetate and ananti-bloating agent. In some embodiments, the anti-bloating agent ispyrilamine maleate or pamabrom. In some embodiments, the unit dosecomprises about 15 mg pyrilamine maleate. In some embodiments, the unitdose comprises about 25 mg pamabrom. In some embodiments, the unit dosecomprises an oxaloacetate, a pain reliever and an anti-bloating agent.In some embodiments, the unit dose comprises about 100 mg or about 200mg oxaloacetate. In some embodiments, the unit dose comprises about 200mg oxaloacetate. In some embodiments, the oxaloacetate or oxaloaceticacid is anhydrous enol-oxaloacetate. In some embodiments, thecomposition further comprises a pharmaceutical delivery agent. In someembodiments, the pharmaceutical delivery agent is selected amongst thegroup of capsules, coating agents, encapsulating agents, transdermalpatches, dissolving lozenges, suppositories and biphasic deliverysystems. In some embodiments, the pharmaceutical delivery agent preventsor reduces exposure of the oxaloacetate to water. In some embodiments,the composition further comprises a pH modifier. In some embodiments,wherein the pH modifier is sodium hydroxide or calcium carbonate. Insome embodiments, the PMS is PMDD.

In some aspects, the invention provides an article of manufacture ofoxaloacetate for treating PMS, the article of manufacture comprising acomposition comprising oxaloacetate and a composition comprising a painreliever. In some embodiments, the pain reliever is acetaminophen,ibuprofen, or naproxen. In some embodiments, the composition comprisesabout 500 mg acetaminophen. In some embodiments, the article ofmanufacture comprises about 400 mg ibuprofen. In some embodiments, thearticle of manufacture comprises about 220 mg naproxen sodium. In someaspects, the invention provides an article of manufacture ofoxaloacetate for treating PMS, the article of manufacture comprising acomposition comprising oxaloacetate and a pain reliever. In someaspects, the invention provides an article of manufacture ofoxaloacetate for treating PMS, the article of manufacture comprisingcomposition comprising oxaloacetate and a composition comprising ananti-bloating agent. In some aspects, the invention provides an articleof manufacture of oxaloacetate for treating PMS, the article ofmanufacture comprising composition comprising oxaloacetate and ananti-bloating agent. In some embodiments, the anti-bloating agent ispyrilamine maleate or pamabrom. In some embodiments, the article ofmanufacture comprises about 15 mg pyrilamine maleate. In someembodiments, the article of manufacture comprises about 25 mg pamabrom.In some embodiments, the article of manufacture comprises anoxaloacetate, a pain reliever and an anti-bloating agent. In someembodiments, the article of manufacture comprises about 10 mg to about1000 mg oxaloacetate. In some embodiments, the composition comprisingoxaloacetate comprises about 100 mg or about 200 mg oxaloacetate. Insome embodiments, the composition comprising oxaloacetate comprisesabout 100 mg oxaloacetate. In some embodiments, the oxaloacetate oroxaloacetic acid is anhydrous enol-oxaloacetate. In some embodiments,the composition further comprises a pharmaceutical delivery agent. Insome embodiments, the pharmaceutical delivery agent is selected amongstthe group of capsules, coating agents, encapsulating agents, transdermalpatches, dissolving lozenges, suppositories and biphasic deliverysystems. In some embodiments, the pharmaceutical delivery agent preventsor reduces exposure of the oxaloacetate to water. In some embodiments,the composition further comprises a pH modifier. In some embodiments,wherein the pH modifier is sodium hydroxide or calcium carbonate. Insome embodiments, the article of manufacture is impervious to moisture.In some embodiments, the article of manufacture further comprises adessicant. In some embodiments, the PMS is PMDD.

In some aspects, the invention provides a method for treating thecombination of suicidal ideation and depression in an individual, themethod comprising administering an effective amount of a compositioncomprising an oxaloacetate, and oxaloacctic acid, or an oxaloacetatesalt to an individual in need thereof. In some embodiments, theindividual is experiencing symptoms of PMS. In some embodiments, the PMSis PMDD. In some embodiments, said oxaloacetate or oxaloacctic acid isanhydrous enol-oxaloacetate. In some embodiments, the compositionfurther comprises a pharmaceutical delivery agent. In some embodiments,said pharmaceutical delivery agent is selected amongst the group ofcapsules, coating agents, encapsulating agents, transdermal patches,dissolving lozenges, suppositories and biphasic delivery systems. Insome embodiments, the pharmaceutical delivery agent prevents or reducesexposure of the oxaloacetate to water. In some embodiments, thecomposition further comprises a pH modifier. In some embodiments, the pHmodifier is sodium hydroxide or calcium carbonate. In some embodiments,the composition comprises about 100 or about 200, about 300 or about 400mg oxaloacetate. In some embodiments, about 200 mg oxaloacetate isadministered to the individual per day. In some embodiments, thecomposition is administered over a period of about one day, two days,three days, four days or five days.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the results of a clinical trial evaluating randomized,double-blinded, placebo controlled cross-over trial for PMS emotionalsymptoms with oxaloacetate.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with an aspect of the present invention, there is provideda method of treatment of the symptoms of PMS and PMDD by administeringan oxaloacetate, an oxaloacetic acid, an anhydrous enol-oxaloacetate oran oxaloacetate salt in a person in need thereof. Also provided is acomposition of matter combining said oxaloacetate, oxaloacetic acid,anhydrous enol-oxaloacetate or oxaloacetate salt with either a painreliever or an anti-bloating agent, or a combination thereof.

The symptoms of PMS and PMDD which include the group of symptoms ofmuscle ache, bloating, cramping, acne, tender breasts, bloating,fatigue, difficulty concentrating, diminished impulse control,irritability, anxiety, tension, anger, depression, feeling “out ofcontrol”, insomnia and rapid fluctuations in mood (mood swings).Suicidal thoughts are also sometimes reported. The symptoms typicallyresolve with the start of menstruation. In some embodiment, the methodcomprises administration of oxaloacetate, oxaloacetate salts,oxaloacetic acid and/or anhydrous enol-oxaloacetate in the form of apharmaceutical composition containing one or more pharmaceuticallyacceptable carriers. For some of the symptoms, a combination of matteris used adding a pain reliever and/or anti-bloating agent.

Oxaloacetate participates in many biochemical reactions in the body,including those in the citric cycle within the mitochondria,gluconeogenesis, urea cycle, glyoxylate cycle, amino acid synthesis, andfatty acid synthesis.

The applicant has seen glutamate reduction in patients via oxaloacetatevia three different delivery systems of the anhydrous enol-oxaloacetate;orally in hypromellose capsules, in a lozenge form, and via intravenousinjection.

There is an increase in glucose demand in the cerebellum during the lateluteal phase which correlates with PMS and PMDD symptoms, dropping bloodglucose levels with a compound that promotes lower blood glucose shouldexacerbate these symptoms. Oxaloacetate has been shown in a clinicaltrial to lower fasting glucose levels in diabetics (See Yhoshikawa, K,Studies on Anti-diabetic Effect of Sodium Oxaloacetate, Tohoku J ExpMed, 1968, 96, 127-141), so art teaches against using oxaloacetatecompounds.

Surprisingly, we did see a significant change in PMS and PMDD symptomswith the administration of 100 to 300 mg oxaloacetate, taken eitherorally or sublingually, even though we were dropping glutamate levels inthe brain, and glucose levels in the bloodstream. One skilled in the artwould expect symptoms to become more acute, rather than be reduced withdecreasing glutamate levels and glucose levels as these low levels aretied to PMS and PMDD symptoms.

In some embodiments, oxaloacetate, oxaloacetate salts, oxaloacetic acidand/or anhydrous enol-oxaloacetate are highly effective in treating thesymptoms of acne, tender breasts, fatigue, difficulty concentrating,diminished impulse control, irritability, anxiety, tension, anger,depression, suicidal thoughts, feeling “out of control”, insomnia,cramping and rapid fluctuations in mood associated with PMS and PMDDthat typically only resolve upon menstruation in these women. With theaddition of a pain reliever or anti-bloating agent, the additionalsymptom of bloating is resolved, and tender breasts and cramping arefurther relieved.

Recognizing PMS and PMDD in patients is covered in the Diagnostic andStatistical Manual of Mental Disorders, Fifth Edition, and in journalarticles such as taught by Liang, Bryan M D, “Recognizing and TreatingPremenstrual Dysphoric Disorder”, Hospital Physician, August 2003 pp45-57.

Oxaloacetic Acid, Oxaloacetate and Oxaloacetate Salts

In some embodiments, the present invention provides methods for treatingsymptoms of PMS and methods for treating symptoms of PMS and PMDDcomprising administration of compositions comprising oxaloacetate.Oxaloacetic acid, when dissolved in water, ionizes to oxaloacetate. Theoxaloacetate can be in three forms depending on the pH of the solution.At low pH (<1.5) and low temperature (<4° C.) oxaloacetate hydrates. Athigher pH, oxaloacetic acid in water occurs in three forms, 1) thehydrated form, 2) a keto form, and 3) an enol form. Outside of watersolutions, the solid form of oxaloacetic acid is primarily in the enolform. All forms of oxaloacetic acid and the ion oxaloacetate areabsorbed by the body. The hydrated form is mostly converted once itenters the higher pH of the body outside of the intestinal tract to theketo and enol form. As a specific example, at a pH of 6.9, oxaloaceticacid in water is composed of 5% in the hydrated form, 84% in the ketoform and 11% in the enol form. Enol-oxaloacetate is converted toketo-oxaloacetate with the enzyme enol-keto tautomerase, a ubiquitousenzyme throughout the human body.

While oxaloacetic acid can be given in any of the three forms and beeffective (because the forms change with different pH conditions andenzymatic activity), there is a significant problem with stability thathas prevented the commercialization of the compound as a therapeuticagent. (See Cash, U.S. Pat. No. 9,050,306). Keto-oxaloacetic aciddecarboxylates spontaneously into pyruvate and carbon dioxide, andneither byproduct of the decomposition is effective in alleviating thesymptoms of PMS and PMDD. The stability problems of oxaloacetic acid arewell documented in the literature (See U.S. Pat. No. 9,050,306 andreferences described therein). The lack of stability of oxaloacetic acidhas been a source of difficulty in the preparation of a commercialproduct (Yoshikawa, K, Tohoku J. Exp. Med, (1968) 96:127-141).

The enol and keto form of oxaloacetic acid are tautomers, and in waterform a chemical equilibrium. At a pH of 6.9, oxaloacetic acid in wateris composed of 5% in the hydrated form, 84% in the keto form and 11% inthe enol form. The keto-oxaloacetate decarboxylates quickly to pyruvate.As the keto-oxaloacetate form disappears due to decarboxylation, theenol and hydrated form convert to keto-oxaloacetate, and then alsodecarboxylate into carbon dioxide and pyruvate, until all theoxaloacetate is consumed. Note that neither of the byproducts ofoxaloacetate decarboxylation, carbon dioxide and pyruvate, are effectivein treating the symptoms of PMS and PMDD. If there are divalent cationsin the fluid, which is very common, the decarboxylation of oxaloaceticacid can happen within a day. Salts of oxaloacetic acid, have beentested and are also not stable, despite the teachings of Yoshikawa. Thehydrated form of oxaloacetic acid can be made stable by maintaining itat very low pH, but only for less than one week, at temperatures notexceeding 8° C. However, this does not allow commercial distribution ofthe product to persons needing treatment for the symptoms of PMS andPMDD with oxaloacetic acid supplementation.

Stabile Oxaloacetic Acid, Oxaloacetate and Oxaloacetate Salts

In some embodiments, the current invention makes use of stableoxaloacetic acid for the treatment of symptoms of PMS and PMDD, whichallows for a reasonable shelf life of one year or more. (See Cash, U.S.Pat. No. 9,050,306). In some embodiments, the methods and compositionsfor the treatment of symptoms of PMS and PMDD use anhydrousenol-oxaloacetic acid which is stable at room temperature for a periodexceeding one year. The enol-oxaloacetic acid does not decarboxylatespontaneously and is thus stable if kept dry. Water catalyzes theequilibrium reaction between enol- and keto oxaloacetic acid. Note thatonly the keto form of oxaloacetic acid decarboxylates into pyruvate andcarbon dioxide spontaneously, not the enol-form. There is an energy gapbetween the enol and keto form which is bridged when the compounds areexposed to water, however, this same energy gap prevents the conversionof the enol to keto form when the product is kept dry. Once there is aconversion to the keto form, decarboxylation can spontaneously occur attemperatures above the freezing point of water. Thus, manufacturingoxaloacetate with a water content of less than 2% and keeping theoxaloacetic acid in a solid state and dry through the use of moisturesealants and/or moisture absorbents creates the commercial shelf-stableenol-oxaloacetate form, even at room temperatures. Drying effectivenesscan be increased by increasing the drying time, drying under vacuum, byusing anhydrous washes of isopropyl alcohol or ethyl alcohol to absorbthe remaining water (and then evaporating the alcohol), or by performingmultiple washes with hexane or non-water soluble solvent to physicallyremove the water, typically after an alcohol wash. The non-water solublesolvent would then be evaporated off. The small amount of non-watersoluble solvent wash remaining in the oxaloacetic acid is non-toxic andserves to repel water moisture from entering into the powder to furtherextend shelf life. Hexane is a residual solvent in many commercial foodpreparations including decaffeinated coffee, and is not toxic in smallquantities. Alternatively, the final wash can be performed withliquefied propane, liquefied butane, ethyl acetate, ethane, carbondioxide, or nitrous oxide to reduce the water content.

In practice, the isolation of the oxaloacetate from water in theatmosphere for use in the treatment of symptoms of PMS and PMDD can beeasily achieved after encapsulation of the oxaloacetic acid by sealingthe bottles or placing individual capsules in a plastic blister pack.Reducing the water content below 2% or below 1% along with isolationfrom the atmosphere, will keep the oxaloacetate in the enol form, andwill prevent decarboxylation. Additional measures to preventdecarboxylation include the use of desiccants in the container with theenol-oxaloacetate and the addition of 10% to 90% anhydrous ascorbic acidper weight of oxaloacetic acid, or in some embodiments, 50% anhydrousascorbic acid per weight of oxaloacetic acid. Ascorbic acid acts as anelectron acceptor and reduces the rate of decarboxylation. In someembodiments, the combination of adding anhydrous ascorbic acid, scalingthe container, and using an enol-form oxaloacetic acid below a 1%moisture level combine to yield a shelf-life of the product at 30° C. inexcess of one year.

In some embodiments, the methods and compositions for the treatment ofsymptoms of PMS and PMDD comprise a stabilized sodium oxaloacetate (andother salts, solutions and buffered solutions of oxaloacetic acid).Stabilization can be achieved by a biphasic containment system. Sodiumoxaloacetate for commercial use can be made by using the solid anhydrousenol-form and combining it with a solution of water plus sodiumhydroxide (NaOH) or other basic solution when needed. This can be in theform of a container with two separate compartments, one that containsthe basic solution, and one that contains the anhydrousenol-oxaloacetate separated by a breakable barrier. When sodiumoxaloacetate (or other salt) is needed, the barrier between the basicsolution and the anhydrous oxaloacetate is broken, and oxaloacetate saltis quickly formed in solution. The solubility of oxaloacetic acid inwater is 100 mg/ml, allowing rapid digestion of the anhydrousenol-oxaloacetic acid. In some embodiments, a biphasic containmentsystem includes a flexible capsule, such as a gel cap which can becompressed by hand or with teeth to break an inner seal between thesodium hydroxide solution and the solid anhydrate enol-oxaloacetate. Inother embodiments, the biphasic containment system includes anintravenous (IV) bag with two compartments, one with an IV fluid and theother with anhydrous enol-oxaloacetic acid separated by a breakablebarrier. When needed, the breakable barrier is ruptured, and the twocomponents are mixed. The IV fluid can be a buffered solution, anon-buffered solution, an acidic solution, a basic solution or a neutralsolution. In yet another embodiment, the biphasic containment system hastwo separate containers; one for the solid oxaloacetic acid, and one forthe liquids. Two separate containers will allow the solid oxaloaceticacid to be placed in storage below 0° C., while the liquid container iskept at a different temperature. Storing the dry oxaloacetic acid at−20° C. enables the use of commonly available commercial oxaloaceticacid, without the additional drying step of the preparation. Again whenneeded, the two containers are joined and mixed to yield theoxaloacetate salt solution.

Pharmaceutical Compositions and Methods of Administration

Oxaloacetate can be administered to an individual at therapeuticallyeffective doses for the treatment of symptoms of PMS and PMDD. In someembodiments, oxaloacetate is administered to an individual for thetreatment of suicide ideation and depression.

As used herein, “oxaloacetate” includes oxaloacetic acid, the salt ofthe acid, or oxaloacetate in a buffered solution as well as mixturesthereof. In some embodiments of the current invention, the oxaloaceticacid can be in the form of anhydrous enol-oxaloacetic acid.

Effective Dose

A therapeutically effective dose refers to that amount of oxaloacetatesufficient to result in the desired effect such as the amelioration ofsymptoms relating to PMS and PMDD. In some embodiments, the dose is fromabout 100 mg oxaloacetate to about 1,000 mg oxaloacetate. In someembodiments, the dose is from about 100 mg oxaloacetate to about 300 mgoxaloacetate. In some embodiments, the does is less than or equal to anyof about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg,900 mg, or 1000 mg. The oxaloacetate can be in the form of oxaloacetate,oxaloacetic acid, oxaloacetate salt or anhydrous enol-oxaloacetate.

Toxicity and therapeutic efficacy of oxaloacetate for use in thetreatment of PMS or PMDD can be determined by standard pharmaceuticalprocedures in cell cultures or experimental animals, e.g., fordetermining the LD₅₀ (the dose lethal to 50% of the population) and theED₅₀ (the dose therapeutically effective in 50% of the population or PMSor PMDD patients). The dose ratio between toxic and therapeutic effectsis the therapeutic index and it can be expressed as the ratio LD₅₀/ED₅₀.The LD₅₀ of oxaloacetate is above 5 g/kg of body weight. The “noobservable adverse effects level” (NOAEL) in a 90-day sub-chronic ratstudy was 500 mg/kg (the highest dose in the test). Oxaloacetate has avery low toxicity, as would be expected from a chemical involved in theCitric Acid Cycle of every cell.

In some embodiments of the invention, an effective dose of oxaloacetateadministered by a lozenge is from about 0.2 mg to about 50 mg ofoxaloacetate for the treatment of symptoms of PMS and/or PMDD for eachkg of body weight. In some embodiments, the effective dose ofoxaloacetate is between about 1 mg and about 4 mg for each kg of bodyweight. Due to the acidity of the compound, the effective dose must bepH balanced. In some embodiments, effective oral dosing ranges fromabout 0.2 mg to about 50 mg of oxaloacetate for each kg of body weight.In some embodiments, the effective dosage range between about 1 mg toabout 4 mg of oxaloacetate for each kg of body weight. For example, anadult female weighing approximately 70 kg would be administered betweenabout 70 mg to about 280 mg of oxaloacetate orally per day. Dermally,topical formulations comprising concentrations of about 0.2 to 16 mM ofoxaloacetate are effective but again need to be pH balanced and in atransdermal system that is extremely low in water content (to preventdegradation of the oxaloacetate).

Formulations

Pharmaceutical compositions for use in accordance with the presentinvention may be formulated in conventional manner using one or morephysiologically acceptable carriers or excipients. Thus, oxaloacetateand its physiologically acceptable salts and solvates may be formulatedfor administration by inhalation or insufflation (either through themouth or the nose) or oral, buccal, topical, transdermal, parenteral, orrectal administration. In the case of inhalation, the administration ofoxaloacetate will provide aging benefits directly to lung tissue, evenif the dosage of oxaloacetate administered is less than is needed tobenefit the entire organism.

Oxaloacetate is acidic with a pH in water about 2.3. The acidity isunlikely to affect organisms that ingest the compound in beneficialamounts as the interior conditions of the stomach are also very acidic(around 1.0). The acidity may affect other tissues, including but notlimited to the skin or lungs, that may allow delivery of the directapplication of oxaloacetate. Therefore, in another embodiment, acomposition of matter can be created by mixing oxaloacetate with abuffer solution or a base or used as a salt of oxaloacetate so thedelivered compound is not caustic. This will enable higherconcentrations of oxaloacetate to be delivered safely to the organism,especially if the oxaloacetate is not delivered by oral ingestion.

For oral administration for the treatment of symptoms of PMS and/orPMDD, the pharmaceutical compositions may take the form of, for example,tablets or capsules prepared by conventional means with pharmaceuticallyacceptable excipients such as binding agents (e.g., pregelatinized maizestarch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers(e.g., lactose, microcrystalline cellulose or calcium hydrogenphosphate); lubricants (e.g., magnesium stearate, talc or silica);disintegrants (e.g., potato starch or sodium starch glycollate); orwetting agents (e.g., sodium lauryl sulphate). The tablets may be coatedby methods well known in the art. Liquid preparations for oraladministration may take the form of, for example, non-water solutions,syrups or suspensions, or they may be presented as a dry product forconstitution with water or other suitable vehicle immediately before use(due to decarboxylation concerns). Water acts as a catalyst which allowsfor the conversion of solid enol-oxaloacetate to convert to the liquidketo-oxaloacetate form which spontaneously decarboxylates into pyruvateand carbon dioxide. Such non-water liquid preparations may be preparedby conventional means with pharmaceutically acceptable additives such assuspending agents (e.g., sorbitol syrup, cellulose derivatives orhydrogenated edible fats); emulsifying agents (e.g., lecithin oracacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethylalcohol or fractionated vegetable oils); and preservatives (e.g., methylor propyl-p-hydroxybenzoates or sorbic acid). The preparations may alsocontain buffer salts, flavoring, coloring and sweetening agents asappropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound. For buccal administration thecompositions may take the form of tablets or lozenges formulated inconventional manner. For administration by inhalation, the compounds foruse according to the present invention are conveniently delivered in theform of an aerosol spray presentation from pressurized packs or anebuliser, with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol the dosage unit may be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof e.g. gelatin for use in an inhaler or insufflator may be formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

A topical application through a trans-dermal patch or cream is yetanother embodiment for administration of oxaloacetate for treating thesymptoms of PMS and PMDD. The topical pharmaceutical compositions of thepresent invention may be made into a wide variety of product types.These include, but are not limited to lotions, creams, beach oils, gels,sticks, sprays, ointments, pastes, and mousses. These product types maycomprise several types of pharmaceutical carrier systems including, butnot limited to solutions, emulsions, gels and solids. The topicalpharmaceutical compositions of the present invention formulated assolutions typically include a pharmaceutically-acceptable organicsolvent. The terms “pharmaceutically-acceptable organic solvent” referto a solvent which is capable of having dissolved therein theoxaloacetate, and possesses acceptable safety properties (e.g.,irritation and sensitization characteristics). Examples of a suitablepharmaceutically acceptable organic solvent include, for example,monohydric alcohols, such as ethanol, and polyhydric alcohols, such asglycols. If the topical pharmaceutical compositions of the presentdisclosure are formulated as an aerosol and applied to the skin as aspray-on, a propellant is added to a solution composition.

In some embodiments, the oxaloacetate for use in treating symptoms ofPMS and/or PMDD may be formulated from a solution carrier system is acream or ointment. In some embodiments, the cream or ointment is anon-water based cream or ointment. An ointment can comprise a simplebase of animal or vegetable oils or semi-solid hydrocarbons(oleaginous). An ointment can include from about 0.1% to about 2% of athickening agent. Examples of suitable thickening agents include:cellulose derivatives (e.g., methyl cellulose and hydroxypropylmethylcellulose), synthetic high molecular weight polymers (e.g.,carboxyvinyl polymer and polyvinyl alcohol), plant hydrocolloids (e.g.,karaya gum and tragacanth gum), clay thickeners (e.g., colloidalmagnesium aluminum silicate and bentonite), and carboxyvinyl polymers(CARBOPOLS′; sold by B. F. Goodrich Company, such polymers are describedin detail in Brown, U.S. Pat. No. 2,798,053, issued Jul. 2, 1975). Amore complete disclosure of thickening agents useful herein can be foundin Sagarin, Cosmetics, Science and Technology, 2nd Edition, Vol. 1, pp.72-73 (1972). If the carrier is formulated as an emulsion, from about 1%to about 10%, for instance, from about 2% to about 5%, of the carriersystem comprises an emulsifier. Suitable emulsifiers include nonionic,anionic or cationic emulsifiers. Exemplary emulsifiers are disclosed in,for example, McCutcheon's Detergents and Emulsifiers, North AmericanEdition, pages 317-324 (1986). In some embodiments, emulsifiers areanionic or nonionic, although other types can also be employed.

An emulsion carrier system useful in the topical pharmaceuticalcompositions for the treatment of symptoms of PMS and/or PMSS is amicroemulsion carrier system. Such a system comprises from about 9% toabout 15% squalane; from about 25% to about 40% silicone oil; from about8% to about 20% of a fatty alcohol; from about 15% to about 30% ofpolyoxyethylene sorbitan mono-fatty acid (commercially available underthe trade name Tweens) or other nonionics; and from about 7% to about20% water. This carrier system is combined with the therapeutic agentsdescribed above, with the oxaloacetate carried in the non-water portion.

The topical pharmaceutical compositions for the treatment of symptoms ofPMS and/or PMDD can also include a safe and effective amount of apenetration enhancing agent. Other conventional skin care productadditives may also be included in the compositions of the presentinvention. For example, collagen, elastin, hydrolysates, primrose oil,jojoba oil, epidermal growth factor, soybean saponins,mucopolysaccharides, and mixtures thereof may be used. Various vitaminscan also be included in the compositions of the present invention. Forexample, Vitamin A, and derivatives thereof, Vitamin B2, biotin,pantothenic, Vitamin D, and mixtures thereof can be used.

In yet a further embodiment of the current invention, the oxaloacetatedelivered topically can be mixed with a penetration enhancing agent suchas dimethylsulfoxide (DMSO), combinations of sucrose fatty acid esterswith a sulfoxide or phosphoric oxide, or eugenol, that allows fastermigration of the oxaloacetate into the dermal tissues and then furtherinto deeper cellular tissues.

In some embodiments, the disclosed compounds are administered through atopical delivery system for the treatment of symptoms of PMS and PMDD.Implantable or injectable polymer matrices, and transdermalformulations, from which active ingredients are slowly released are alsowell known and can be used in the disclosed methods. The controlledrelease components described above can be used as the means to deliverthe disclosed compounds. The compositions can further include componentsadapted to improve the stability or effectiveness of the appliedformulation, such as preservatives, antioxidants, skin penetrationenhancers and sustained release materials. Examples of such componentsare described in the following reference works hereby incorporated byreference: Martindale—The Extra Pharmacopoeia (Pharmaceutical Press,London 1993) and Martin (ed.), Remington's Pharmaceutical Sciences.

Controlled release preparations can be achieved by the use of polymersto complex or absorb oxaloacetate. The controlled delivery can beexercised by selecting appropriate macromolecule such as polyesters,polyamino acids, polyvinylpyrrolidone, ethylenevinyl acetate,methylcellulose, carboxymethylcellulose, and protamine sulfate, and theconcentration of these macromolecule as well as the methods ofincorporation are selected in order to control release of activecompound.

In another embodiment, transdermal patches, steady state reservoirssandwiched between an impervious backing and a membrane face, andtransdermal formulations, can also be used to deliver oxaloacetate forthe treatment of symptoms of PMS and/or PMDD. Transdermal administrationsystems are well known in the art. Occlusive transdermal patches for theadministration of an active agent to the skin or mucosa are described inU.S. Pat. Nos. 4,573,996, 4,597,961 and 4,839,174, which are herebyincorporated by reference. One type of transdermal patch is a polymermatrix in which the active agent is dissolved in a polymer matrixthrough which the active ingredient diffuses to the skin. Suchtransdermal patches are disclosed in U.S. Pat. Nos. 4,839,174, 4,908,213and 4,943,435, which are hereby incorporated by reference. In oneembodiment, the steady state reservoir carries doses of oxaloacetate indoses from about 2 mg to 40 mg per day.

Present transdermal patch systems are designed to deliver smaller dosesover longer periods of time, up to days and weeks. A rate-controllingouter microporous membrane, or micropockets of the disclosedoxaloacetate dispersed throughout a silicone polymer matrix, can be usedto control the release rate. Such rate-controlling means are describedin U.S. Pat. No. 5,676,969, which is hereby incorporated by reference.In another embodiment, the oxaloacetate is released from the patch intothe skin of the patient in about 20-30 minutes or less.

These transdermal patches and formulations can be used with or withoutuse of a penetration enhancer such as dimethylsulfoxide (DMSO),combinations of sucrose fatty acid esters with a sulfoxide or phosphoricoxide, or eugenol. The use of electrolytic transdermal patches is alsowithin the scope of the methods disclosed herein. Electrolytictransdermal patches are described in U.S. Pat. Nos. 5,474,527,5,336,168, and 5,328,454, the entire contents of which are herebyincorporated by reference.

Oxaloacetate may be formulated for parenteral administration for thetreatment of symptoms of PMS and/or PMDD by injection, e.g., by bolusinjection or continuous infusion. The injected oxaloacetate can be mixedwith other beneficial agents prior to injection including but notlimited to antibiotics and other medications, saline solutions, bloodplasma, and other fluids. Immediate contact of elevated levels ofoxaloacetate with the vascular system cells will result in the reductionin age-related diseases such as hardening of the arteries, even if theamounts of oxaloacetate are insufficient to provide age-related benefitsto the entire organism. Formulations for injection may be presented inunit dosage form, e.g., in ampoules or in multi-dose containers, with anadded preservative. The compositions may take such forms as suspensions,solutions or emulsions in oily or non-aqueous vehicles, and may containformulatory agents such as suspending, stabilizing and/or dispersingagents. Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before immediate use.

Oxaloacetate may also be formulated in rectal compositions such assuppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter or other glycerides.

In addition to the formulations described previously, oxaloacetate mayalso be formulated as a depot preparation. Such long acting formulationsmay be administered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. Thus, for example, thecompounds may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

The compositions for the treatment of symptoms of PMS and/or PMDD may,if desired, be presented in a pack or dispenser device which may containone or more unit dosage forms containing the active ingredient. The packmay for example comprise metal or plastic foil, such as a blister pack.The pack or dispenser device may be accompanied by instructions foradministration.

In another embodiment of the current invention, oxaloacetate can becombined with a pain reliever to decrease cramping pain, headache pain,or muscle pain occurring in PMS and PMDD. Said pain relievers caninclude ibuprofen, acetaminophen, aspirin, indomethacin, oxyphenbutazoneand naproxen. Examples of pain relievers used in formulations for PMSand PMDD and their dosage can be found in U.S. Pat. No. 5,155,105 byJones et al. and other pain relievers used in formulations are known inthe art.

In some embodiments, the pain reliever is acetaminophen, ibuprofen, ornaproxen. In some embodiments, about 100 mg to about 1000 mgacetaminophen is administered to the individual in combination withoxaloacetate treatment. In some embodiments, about any of 100 mg, 200mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mgacetaminophen is administered to the individual in combination withoxaloacetate treatment. In some embodiments, about 500 mg acetaminophenis administered to the individual in combination with oxaloacetatetreatment. In some embodiments, about 100 mg to about 1000 mg ibuprofenis administered to the individual in combination with oxaloacetatetreatment. In some embodiments, about any of 100 mg, 200 mg, 300 mg, 400mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg ibuprofen isadministered to the individual in combination with oxaloacetatetreatment. In some embodiments, about 400 mg ibuprofen is administeredto the individual in combination with oxaloacetate treatment. In someembodiments, about 100 mg to about 500 mg naproxen (e.g., naproxensodium) is administered to the individual in combination withoxaloacetate treatment. In some embodiments, about any of 100 mg, 140mg, 180 mg, 220 mg, 260 mg, or 300 mg naproxen is administered to theindividual in combination with oxaloacetate treatment. In someembodiments, about 220 mg acetaminophen is administered to theindividual in combination with oxaloacetate treatment.

In yet another embodiment of the current invention, oxaloacetate can becombined with a diuretic or anti-bloating compound to reduce periodicwater retention or buildup in the body. Such diuretics can include bothpharmacological and/or nutritional herbal compounds. Said diuretics caninclude potassium compounds (such as potassium citrate) pamabrom,pyrilamine maleate, caffeine, and hydrochlorothiazide. Typicallypotassium compounds are limited to deliver no more than 100 mg ofpotassium per dose. The dosage and uses of other diuretics can be foundin U.S. Pat. No. 5,155,105 by Jones et al. Herbal nutritionals can alsohave a diuretic effect. These would include but not be limited todandelion root and leaf, juniper berry, cranberry powder (fruit),hibiscus extract (flower), chamomile (flower), grape seed powder,parsley, red raspberry powder (leaf), goldenrod, Uva Ursi extract(leaf), Agathosma Betulina (leaf), Fucus Vesiculosus, Mango Seed powder,and paprika. Other nutritional and pharmacological diuretics are knownin the art.

In some embodiments, the anti-bloating agent is pyrilamine maleate orpamabrom (1:1 mixture of 2-amino-2-methyl-1-propanol and8-bromotheophyllinate). In some embodiments, about 5 mg to about 25 mgpyrilamine maleate is administered to the individual in combination withoxaloacetate treatment. In some embodiments, about any of 5 mg, 10 mg,15 mg, 20 mg, or 25 mg pyrilamine maleate is administered to theindividual in combination with oxaloacetate treatment. In someembodiments, about 15 mg pyrilamine maleate is administered to theindividual in combination with oxaloacetate treatment. In someembodiments, about 10 mg to about 50 mg pamabrom is administered to theindividual in combination with oxaloacetate treatment. In someembodiments, about any of 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40mg, 45 mg or 500 mg pamabrom is administered to the individual incombination with oxaloacetate treatment. In some embodiments, about 25mg pamabrom is administered to the individual in combination withoxaloacetate treatment.

In some embodiments, the oxaloacetate is administered to the individualin combination with a pain reliever and an anti-bloating agent. Forexample, one or more of acetaminophen, ibuprofen, or naproxen and one ormore of pyrilamine maleate or pamabrom.

While others in the art have combined pain relievers with diuretics(such as U.S. Pat. No. 5,155,105), to deal with some of the symptoms ofPMS and PMDD, including bloating, and head, muscle and cramping pain,these combinations have had no effect on mood swings, depression,anxiety, fatigue and anger, which are affected by oxaloacetatesupplementation in the current invention. Combination of oxaloacetatewith pain relievers and diuretics provide a more effective overallsolution to the problems of PMS and PMDD because it also address theemotional side of PMS and PMDD.

As used herein, “treatment” is an approach for obtaining beneficial ordesired clinical results. For purposes of this invention, beneficial ordesired clinical results include, but are not limited to, alleviation ofsymptoms of PMS and PMDD, diminishment of symptoms of PMS and PMDD, andstabilized (e.g., not worsening) symptoms of PMS and PMDD.

Reference to “about” a value or parameter herein includes (anddescribes) variations that are directed to that value or parameter perse. For example, description referring to “about X” includes descriptionof “X”.

As used herein and in the appended claims, the singular forms “a,” “or,”and “the” include plural referents unless the context clearly dictatesotherwise. It is understood that aspects and variations of the inventiondescribed herein include “consisting” and/or “consisting essentially of”aspects and variations.

While the present invention has been particularly shown and describedwith reference to exemplary embodiments thereof, it will be understoodby those of ordinary skill in the art that various changes in form anddetails may be made therein without departing from the spirit and scopeof the present invention as defined by the following claims.

EXAMPLES

Below are some case studies and a human trial, both of which showsignificant improvement in symptoms. While acne can be measured byinspection, the other symptoms rely upon the internal feelings of thepatient. To measure symptoms that deal with tender breasts, fatigue,difficulty concentrating, diminished impulse control, irritability,anxiety, tension, anger, depression, suicidal thoughts, feeling “out ofcontrol”, insomnia, cramping and rapid fluctuations in mood, one skilledin the art must rely on the interpretation of patient. This can be donethrough an interview with an expert, such as a medical doctor, orthrough validated survey forms that specifically address these symptoms.Examples of these forms that have been validated by independent clinicaltrial include:

-   -   Buss Perry Aggression Questionnaire (Anger)    -   Clinical Anger Scale (Anger)    -   Cohen-Perceived-Stress Scale (Anxiety)    -   Generalized-Anxiety-Scale (Anxiety)    -   Generalized Anxiety Disorder 7-item (GAD-7) scale (Anxiety)    -   Beck's Depression Inventory (Depression)    -   Center for Epidemiologic Studies Depression Scale (Depression)    -   Hospital Anxiety and Depression Scale (Anxiety and Depression)    -   Premenstrual Assessment Form (anger, depression, fatigue and        anxiety)    -   Mood Calendar Tracking (anger, depression, fatigue and anxiety)

Example 1

In a clinical trial, 30 women with PMS were first evaluated for PMS andthen presented with the nutritional supplement “benaGene” (100 mganhydrous enol-oxaloacetate with a pharmaceutically acceptable excipientof 150 mg anhydrous ascorbic acid). Only one patient did not report asubstantial improvement, indicative of a positive response rate of 97%.Typically, in 30-60 minutes from taking 1 to 2 capsules, once per day,many or all PMS symptoms would either resolve fully or would be reducedsignificantly. The patients would only take the supplement during daysthey experienced PMS symptoms, and not the rest of the month. 3 capsulesdid not produce a superior response to 2 capsules.

Example 2

A 28 year-old woman experienced severe anger and depression one day amonth, right before her period, every month. She took two capsules of100 mg anhydrous enol-oxaloacetate on that day. She reported that whilethe anger and depression were not completely resolved, they were reducedin intensity to the point where she could manage the symptoms easily.

Example 3

A woman diagnosed with PMDD had a history of extreme cramping (painlevel 10), suicidal thoughts, and difficulty with anger and anxiety. Thecramping was not relieved by Midol or Aspirin. The woman was despondenteven after her symptoms of PMDD left because of guilt over her behaviorduring this time period. She took 200 mg oxaloacetate in a hypromellosecapsule carrier, and experienced immediate relief from all symptoms. Shereported that it was like a 1,000 pound weight being taken off hershoulders.

Example 4

The woman in Example 3 continued to take oxaloacetate each month for thenext three months and monitored her progress. She took one pill startingabout 10 days before her period, and continued taking 1 pill daily untilthe first sign of PMS, when she increased the dosage to 2 capsules perday until the 2nd day of her period. The symptoms of PMDD completelyresolved. She reported that “I am no longer a suicidal, psychotic crazyperson every month. And I know it is the supplements because this willbe the 3rd month with no PMDD and that is NOT a coincidence.”

Example 5

A woman presented with severe PMDD ever since she was 13 years old. Sheis now 26. Typically, the patient had to take-off from work 3 days outof each month, and self-seclude, because she could not be with people.She started taking 2 capsules benaGene (each 100 mg anhydrousenol-oxaloacetate with acceptable pharmacological carriers). Allsymptoms resolved and she no longer has to take off from work. Theimprovements with anhydrous enol-oxaloacetate have continued for over 2years with this patient.

Example 6

A 25-year old woman presented with severe anxiety attacks and fatigueduring the week before menstruation. At the start of these panic attacksor during extreme fatigue, she placed two lozenges of 100 mg anhydrousenol-oxaloacetate with a suitable pH adjustment and pharmaceuticalcarrier under her tongue for 5 minutes. The panic attack subsided inless than 5 minutes and fatigue was greatly reduced.

Example 7

A randomized, double blinded placebo-controlled crossover trial wasconducted using 200 mg oxaloacetate per day as the active ingredient,and rice flour as the placebo ingredient. An Institutional Review Board(IRB) has approved the clinical plan, and patients have signed the humanconsent forms.

Patients were located from across the United States. Consent forms andsurvey questionnaires were filled out on-line. The patients and the leadinvestigator were unaware of which product, Active or Placebo, thepatients were receiving.

Inclusion Criteria for the trial:

-   -   Able to give informed consent and follow instructions per the        protocol    -   Female with history of mood swings, anxiety or depressed mood        associated with PMS    -   Ages 21 to 50 at the start of the study    -   Not pregnant

Exclusion Criteria for the trial:

-   -   A formal diagnosis of Major Depression    -   Previously taken Oxaloacetate as a supplement    -   Participation in other drug studies or use of other        investigational products within 30 days prior to baseline    -   If unwilling to discontinue use of other nutritional supplements        taken for the purpose of PMS modulation during the study    -   Any unstable or clinically significant condition that would        impair the subject's ability to comply with study follow up.    -   No diagnosis of Premenstrual Dysphoric Disorder (PMDD) (a severe        form of PMS).

After signing the human consent forms, the patient took four differentsurveys to assess their current emotional state during PMS.

-   -   The Beck Depression Inventory modified to examine the week prior        to the woman's period (21 questions)    -   The Cohen Perceived Stress form, modified to examine the week        prior to the woman's period (10 questions).    -   The Generalized Anxiety Disorder 7-Item Scale modified to        examine the week prior to the woman's period (7 questions).    -   The Buss Perry Aggression questionnaire modified to examine the        week prior to the woman's period (29 questions).

The time to fill out the composite 4-survey questionnaire is less than30 minutes.

The questionnaires are filled out on-line and made available toinvestigator team. The women in the study did not have access to thequestionnaires they previously completed.

After a “baseline” 4-survey questionnaire was completed by the women,they would be randomly sent either the Active oxaloacetate compound (200mg oxaloacetate) or the Placebo (200 mg rice flour). The women wouldtake a daily dose of the compound received, starting with theirmenstrual period, and continuing daily until the following menstrualperiod. At that following menstrual period, the women would againcomplete the 4-survey questionnaire.

At this point in the clinical trial, the women would have received thesecond shipment of whatever product they did not test previously-Riceflour capsules for those that initially received oxaloacetate, andoxaloacetate capsules for those that received rice flour capsules. Thisis a “cross-over” type design. The women take the new product staring ona menstrual period, and continue taking it daily until a followingmenstrual period. The then again complete the 4-survey questionnaire.

In this trial, each woman completed a baseline survey, and a surveyafter approximately 28 days for oxaloacetate, and a survey afterapproximately 28 days for rice flour. 26 women completed the study. Halfof the women took oxaloacetate first, and the other half took a placebofirst.

Table 1 shows the results of this trial. FIG. 1 shows the resultsgraphically. P values were calculated using a student's T test, using atwo-tailed distribution with paring of the data to the individual.

TABLE 1 Clinical results of a randomized, double-blinded, placebocontrolled cross-over trial for PMS emotional symptoms withoxaloacetate. Reduction from Reduction from Reduction from baselinebaseline Placebo Oxaloacetate P Value Placebo P Value Oxaloacetate PValue Beck's Depression 50.88% 1.5E−06 34.01% 0.0034 25.57% 0.11 Inventory Cohen Perceived Stress 34.35% 2.9E−08 20.46% 0.0054 16.51%0.096 Generalized Anxiety 49.73% 1.9E−07 30.11% 0.0018 28.08% 0.042Disorder Buss-Perry Aggression 15.10% 0.00016  6.49% 0.11   9.22% 0.1 Scale

As can be seen by the results, oxaloacetate supplementation at 200 mgper day was highly statistically significant in reducing the PMSsymptoms of depressed mood, perceived stress, anxiety and aggression(anger). The oxaloacetate results were consistently improved overplacebo, as were the p values showing significance.

Based on review of this data, and on submitted animal and cellular work,the US FDA concurred with the following structure/function claim allowedto be placed on the oxaloacetate product bottle:

“Oxaloacetate may help alleviate the mild to moderate psychologicaland/or behavioral symptoms associated with Premenstrual Syndrome (PMS).”

Example 8

The clinical trial of Example 7 was repeated with 19 women, except thatthe trial was single blinded. The placebo was sent to all women first,and the oxaloacetate active second. The trial was modified in thismanner because in the previous trial, it was calculated thatoxaloacetate supplementation had a beneficial effect beyond the time ofingestion. This should not have come as a complete surprise to us, asoxaloacetate exerts a beneficial effect on gene expression (movementtowards the calorie restriction metabolic state) that can have positiveeffects for several weeks after discontinuation of the product. Tobetter measure the oxaloacetate effect, therefore, oxaloacetate wasgiven second in this trial.

The results of this trial mirror the results of the first trial, againindicating that oxaloacetate successfully reduces the emotional symptomsof PMS.

TABLE 2 Clinical results of a single-blinded, placebo controlledcross-over trial for PMS emotional symptoms with oxaloacetate. Reductionfrom Reduction from Reduction from baseline baseline PlaceboOxaloacetate P Value Placebo P Value Oxaloacetate P Value Beck'sDepression 54.42% 0.0000002 27.51% 0.0006 37.12% 0.012  Inventory CohenPerceived Stress 36.67% 0.0000004 16.20% 0.0013 24.40% 0.00009Generalized Anxiety 54.23% 0.0000021 26.15% 0.015  38.02% 0.008 Disorder Buss-Perry Aggression 17.81% 0.0022    4.36% 0.18  14.06%0.017  ScaleP values were calculated using a student's T test, using a two-taileddistribution with paring of the data to the individual.

Example 9

In the clinical trials within Examples 7 and 8, the Beck's DepressionInventory was used. One portion of the Beck's Depression Inventoryspecifically deals with “Suicidal Ideation” (thoughts about committingsuicide). The survey scores the relative severity of suicidal ideationvia numerical scoring as follows:

-   -   Score Value    -   0 I don't have any thoughts of killing myself.    -   1 I have thoughts of killing myself, but I would not carry them        out.    -   2 I would like to kill myself    -   3 I would kill myself if 1 had the chance.

The results of Clinical Trial 1 and 2 were compiled to examine theSuicidal Ideation of the women who participated in this clinical trial.Out of the 45 women in both trials, 31 women experienced a score above 0in the baseline survey. No women in the completed study who scored 0 inthe baseline study increased their suicidal ideation score. In order toexamine suicidal ideation statistically, women with a 0 score on theirbaseline survey were removed from the analysis. P values were calculatedusing a student's T test, using a two-tailed distribution with paring ofthe data to the individual.

TABLE 3 Oxaloacetate reduces Suicidal Ideation over initial baselinemeasurements Reduction from Baseline P P Oxaloacetate Value PlaceboValue 47.90% 0.000038 35.40% 0.0025

As can be seen, oxaloacetate is highly significant in reducing suicidalideation over baseline values. The improvement is better than placebo inboth scoring and in p value. Of particular interest in this small studywas that with oxaloacetate two of the three women that initially statedthat “I would kill myself if I had the chance” (3 points) moved theiranswer to “I don't have any thoughts of killing myself” (0 points). Theother one woman that initially scored a 3 was reduced to a 1 point withoxaloacetate, reduced to “I have thoughts of killing myself, but I wouldnot carry them out.

Reduction in suicidal ideation may save the lives of these women. It isunexpected and novel that oxaloacetate both reduced depressed mood, andalso reduced suicidal ideation, as typically medications that lowerdepression increase suicidal ideation.

What is claimed is:
 1. A method for treating Premenstrual DysphoricDisorder (PMDD) in an individual, the method comprising administering aneffective amount of a composition comprising an oxaloacetate, anoxaloacetic acid, or an oxaloacetate salt in the individual in needthereof.
 2. A method for treating one or more symptoms of PMDD in anindividual, the method comprising administering an effective amount of acomposition comprising an oxaloacetate, an oxaloacetic acid, or anoxaloacetate salt to an individual in need thereof; wherein the one ormore symptoms of PMS include one or more of acne, tender breasts,bloating, fatigue, difficulty concentrating, diminished impulse control,irritability, anxiety, tension, anger, depression, suicidal thoughts,insomnia, or cramping.
 3. The method of claim 2, wherein the method isfor treating two or more symptoms of PMS in an individual, wherein thetwo or more symptoms of PMS include two or more of acne, tender breasts,bloating, fatigue, difficulty concentrating, diminished impulse control,irritability, anxiety, tension, anger, depression, suicidal thoughts,insomnia, or cramping.
 4. The method of claim 3, wherein the method isfor treating three or more symptoms of PMS in an individual, wherein thethree or more symptoms of PMS include three or more of acne, tenderbreasts, bloating, fatigue, difficulty concentrating, diminished impulsecontrol, irritability, anxiety, tension, anger, depression, suicidalthoughts, insomnia, or cramping.
 5. The method of claim 2, wherein thesymptoms of PMS include acne, bloating, fatigue, irritability, anxiety,anger, depression, insomnia or cramping.
 6. The method of claim 2,wherein the one or more symptoms of PMS further comprises mood swings.7. The method of claim 6, wherein said oxaloacetate or oxaloacetic acidis anhydrous enol-oxaloacetate.
 8. The method of claim 1, wherein thecomposition further comprises a pharmaceutical delivery agent.
 9. Themethod of claim 8 wherein said pharmaceutical delivery agent is selectedamongst the group of capsules, coating agents, encapsulating agents,transdermal patches, dissolving lozenges, suppositories and biphasicdelivery systems.
 10. The method of claim 8, wherein the pharmaceuticaldelivery agent prevents or reduces exposure of the oxaloacetate towater.
 11. The method of claim 1, wherein the composition furthercomprises a pH modifier.
 12. The method of claim 11, wherein the pHmodifier is calcium carbonate.
 13. The method of claim 1, wherein thecomposition comprises about 100 or about 200, about 300 or about 400 mgoxaloacetate.
 14. The method of claim 1, wherein about 200 mgoxaloacetate is administered to the individual per day.
 15. The methodof claim 1, wherein the composition is administered over a period ofabout one day, two days, three days, four days or five days.
 16. Themethod of claim 1, wherein the composition is administered to theindividual about one day, two days, three days, four days or five daysprior to menses.
 17. The method of claim 1, wherein administration ofthe composition is initiated upon detection of one or more symptoms ofPMS.
 18. The method of claim 1, wherein the composition is administeredin combination with a pain reliever.
 19. The method of claim 18, whereinthe pain reliever is acetaminophen, ibuprofen, or naproxen.
 20. Themethod of claim 18, wherein about 500 mg acetaminophen, about 400 mgibuprofen, or about 220 mg naproxen sodium is administered to theindividual.
 21. The method of claim 1, wherein the composition isadministered in combination with an anti-bloating agent.
 22. The methodof claim 21, wherein the anti-bloating agent is pyrilamine maleate orpamabrom.
 23. The method of claim 21, wherein about 15 mg pyrilaminemaleate or about 25 mg pamabrom is administered to the individual.